A Novel Loss-of-Function Mutation in HOXB1 Associated with Autosomal Recessive Hereditary Congenital Facial Palsy in a Large Iranian Family

Abstract

Hereditary congenital facial palsy (HCFP) is a rare congenital cranial dysinnervation disorder, recognisable by non-progressive isolated facial nerve palsy (cranial nerve VII). It is caused by developmental abnormalities of the facial nerve nucleus and its nerve. So far, 4 homozygous mutations have been identified in 5 unrelated families (12 patients) with HCFP worldwide. In this study, a large Iranian consanguineous kindred with 5 members affected by HCFP underwent thorough clinical and genetic evaluation. The candidate gene HOXB1 was screened and analysed by Sanger sequencing. As in previous cases, the most remarkable findings in the affected members of the family were mask-like faces, bilateral facial palsy with variable sensorineural hearing loss, and some dysmorphic features. Direct sequencing of the candidate gene HOXB1 identified a novel homozygous frameshift mutation (c.296_302del; p.Y99Wfs*20) which co-segregated with the disease phenotype within the extended family. Our findings expand the mutational spectrum of HOXB1 involved in HCFP and consolidate the role of the gene in the development of autosomal recessive HCFP. Moreover, the truncating mutation identified in this family leads to a broadly similar presentation and severity observed in previous patients with nonsense and missense mutations. This study characterises and defines the phenotypic features of this rare syndrome in a larger family than has previously been reported.

Keywords: Autosomal recessive; Congenital facial palsy; HOXB1; Moebius syndrome.

Fig. 1

A Pedigree of the Iranian family with 5 individuals affected by hereditary congenital facial palsy (indicated as solid black symbols). Segregation of the loss-of-function mutation in the family with the mutant allele is shown by + and the wild-type allele is shown by −. The ages of the affected individuals are shown below the symbols. B A section of Sanger sequencing chromatograms for the homozygous mutation (bottom) and wild type (top) are depicted and demonstrate the deletion (box). C Pictures of the patients corresponding to the pedigree.

Fig. 2

A schematic representation of HOXB10 homozygous mutations identified so far indicated by the red arrows.